August 21, 2013: Removed reference to ASSIST in section IV.3, since ASSIST is currently only available for multi-project applications.

May 30, 2013 (NOT-OD-13-074) -
NIH to Require Use of Updated Electronic Application Forms for Due Dates on or after September 25, 2013. Forms-C applications are required for due dates on or after September 25, 2013.

This funding opportunity announcement (FOA) encourages
Research Project Grant (R01) applications from institutions/ organizations
addressing preclinical research in model organisms of neurodevelopmental
disorders. Applications submitted to this FOA should propose to develop,
validate, and/or calibrate outcome measures, surrogate markers, and
biomarkers in model organisms that can inform and effectively translate to
human clinical trials for individuals with intellectual and developmental
disabilities (IDD). In addition, applications may propose to conduct
rigorous, controlled and standardized preclinical animal trials designed for
safety, toxicity, and efficacy prediction or to perform an independent
validation of efficacy in animals prior to human clinical trials. The goal of
this FOA is to accelerate and improve the preclinical testing of candidate
treatments and therapeutic compounds in order to move promising new drug
therapies into clinical trials. Potential applicants may be interested in the
FOA “Outcome Measures For Use In Treatment Trials of Individuals with
Intellectual and Developmental Disabilities”.

Key Dates

Posted Date

April 25, 2013

Open Date (Earliest Submission Date)

May 5, 2013

Letter of Intent Due Date(s)

30 days before application due date

Application Due Date(s)

Standard
dates apply, by 5:00 PM local time of applicant organization.

Applicants are encouraged to apply early to allow adequate
time to make any corrections to errors found in the application during the
submission process by the due date.

It is critical that applicants follow the instructions in
the SF424
(R&R) Application Guide, except where instructed to do otherwise (in
this FOA or in a Notice from the NIH
Guide for Grants and Contracts). Conformance to all requirements (both
in the Application Guide and the FOA) is required and strictly enforced. Applicants
must read and follow all application instructions in the Application Guide as
well as any program-specific instructions noted in Section IV. When the program-specific
instructions deviate from those in the Application Guide, follow the
program-specific instructions. Applications that do not comply with
these instructions may be delayed or not accepted for review.

This FOA encourages investigator-initiated R01 applications
that propose to identify, validate and/or calibrate physiologic and/or
behavioral measures in preclinical animal models of disorders associated with
intellectual and developmental disabilities (IDD), particularly in the
pediatric population. It specifically targets the development of outcome
measures or biomarkers that can serve as informative endpoints in preclinical
trials of therapeutic compounds and will predict the safety and efficacy of
interventions in human clinical trials for these disorders. This FOA will focus
ongoing clinical and translational research on a neglected area essential for therapy
and pharmacological treatment development. Potential applicants may be
interested in FOA (PAR-13-213)
“Outcome Measures for Use in Treatment Trials of Individuals with Intellectual
and Developmental Disabilities”.

Background

Over the past several decades, major advances have been made
in finding the genetic and environmental causes of many forms of IDD in
children and adults. Historically, treatment has focused on alleviating
symptoms in affected individuals. More recently, however, a great deal has been
learned about the mechanisms and pathways that underlie disorders such as Down,
Fragile X, Rett, Angelman and Prader-Willi syndromes, and hypoxic/ischemic
injuries leading to IDD. Researchers have created and characterized mice, flies
and other organisms with genetic mutations that model human neurodevelopmental
disorders (e.g., Fmr1 and MeCP2 knockout mouse models of Fragile X syndrome and
Rett syndrome, respectively). Animal models of environmental insults are
available that mimic IDDs in humans (e.g., Rice-Vannucci rat model of
hypoxia/ischemia). Further, investigators have studied these and other
"model animals" to understand the biological bases of the syndromes.
(For a discussion of the use of model animals in psychiatric research, see
Insel TR [2007], Biol. Psychiatry 62:1337-1339.) A 40-year investment in
this research has resulted in greater mechanistic knowledge of the syndromes
and yielded a target-rich environment for developing promising new
rationale-based treatments and pharmacological interventions. Investigators
have begun testing biologic and pharmacologic agents in model animals and cell
lines that permit an understanding of the mechanisms of their action. Scientists
working on several IDD including Fragile X syndrome and Rett syndrome are
actively engaged in therapy development efforts ranging from early
translational studies to human clinical trials. As promising candidate
therapeutics move to preclinical (animal) testing, there is a critical need for
sensitive, reliable and valid outcome measures and/or surrogate markers in
model organisms, particularly measures that can predict safety, toxicity and
efficacy in human trials. Consensus outcome measures that successfully bridge
pre-clinical and clinical studies are lacking for the IDDs. Consequently, there
is a compelling need to develop endpoints and biomarkers in model organisms
that can inform and reliably predict outcomes in human clinical trials.

Objectives

This FOA addresses a significant need in the field: the
identification of sensitive, reliable, and valid endpoints that can be used in
preclinical animal testing and human clinical trials of therapeutic compounds
for IDD. One of the goals of this FOA is to align and validate outcome measures
and biomarkers developed for preclinical animal testing with endpoints
currently or potentially used in human trials; this FOA focuses on preclinical
measures that will predict safety and efficacy of interventions in humans with
developmental disabilities. Applications may also propose preclinical animal
trials or replication studies conducted in a rigorous, controlled and
standardized manner. This FOA is designed to stimulate and accelerate ongoing
clinical and translational research in the IDDs.

Studies in juvenile animal models of pediatric IDD using more
than one mammalian species (e.g., rodents and non-human primates) in parallel
experiments in order to validate a set of measures.

Studies of non-invasive biological and/or physiological measures
of neural circuits underlying treatment response that can be evaluated in both
model animals and pediatric patients.

Investigations of biomarkers or surrogate markers of disease
progression and amelioration that measure treatment response in animals and can
predict outcomes in human clinical trials.

Studies of in vivo, cellular and/or molecular measures in model
organisms that are predictive of safety, efficacy, and toxicity of novel
therapeutics in infants, children and adults with IDD, particularly projects
that focus on neurologic, behavioral, growth and developmental outcomes in
pediatric patient populations.

Development of measures that predict specific adverse effects and
toxicities of pharmacological treatments in IDD patient populations. Investigators
should identify the outcomes to be assessed in preclinical studies and provide
a means for determining the predictive value for the human clinical outcomes.
The measures developed via this initiative may also be relevant to
neurodevelopmental conditions other than the IDD syndromes listed.

Preclinical animal trials of therapeutic compounds for IDD
conducted in a rigorous, controlled and standardized manner; applications may
also propose replication trials of a compound or treatment to allow an
independent validation of efficacy or to address a discrepancy reported in
published studies prior to launching a large scale translational project or
human clinical trial.

It is important to note that biomarker discovery is rapidly
advancing in other disease conditions such as epilepsy and muscular dystrophy.
Thus, prospective applicants may benefit from lessons learned in other, similar
endeavors. Investigators may find it beneficial to establish a multidisciplinary
team that includes, for example, expertise in biochemistry, physiology, and
pharmacology; behavioral and cognitive studies in animals; the design of
clinical trials; clinical aspects of IDD; and other fields as appropriate.

Applicant organizations must complete and maintain the
following registrations as described in the SF 424 (R&R) Application Guide
to be eligible to apply for or receive an award. All registrations must be
completed prior to the application being submitted. Registration can take 6
weeks or more, so applicants should begin the registration process as soon as
possible. The NIH
Policy on Late Submission of Grant Applications states that failure to
complete registrations in advance of a due date is not a valid reason for a
late submission.

Dun and Bradstreet
Universal Numbering System (DUNS) - All registrations require that
applicants be issued a DUNS number. After obtaining a DUNS number, applicants
can begin both SAM and eRA Commons registrations. The same DUNS number must be
used for all registrations, as well as on the grant application.

System for Award Management (SAM) (formerly CCR) – Applicants must complete and maintain an active registration, which requires renewal at least
annually. The renewal process may require as much time as the
initial registration. SAM registration includes the assignment of a Commercial
and Government Entity (CAGE) Code for domestic organizations which have not
already been assigned a CAGE Code.

eRA Commons - Applicants
must have an active DUNS number and SAM registration in order to complete the
eRA Commons registration. Organizations can register with the eRA Commons as
they are working through their SAM or Grants.gov registration. eRA Commons
requires organizations to identify at least one Signing Official (SO) and at
least one Program Director/Principal Investigator (PD/PI) account in order to
submit an application.

Grants.gov – Applicants
must have an active DUNS number and SAM registration in order to complete the
Grants.gov registration.

Program
Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account and should
work with their organizational officials to either create a new account or to
affiliate an existing account with the applicant organization’s eRA Commons
account. If the PD/PI is also the organizational Signing Official, they must
have two distinct eRA Commons accounts, one for each role. Obtaining an eRA
Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal
Investigator)

Any individual(s) with the skills, knowledge, and resources
necessary to carry out the proposed research as the Program Director(s)/Principal
Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to
develop an application for support. Individuals from underrepresented racial
and ethnic groups as well as individuals with disabilities are always
encouraged to apply for NIH support.

Applicant organizations may submit more than one application,
provided that each application is scientifically distinct.

NIH will not accept any application that is essentially the
same as one already reviewed within the past thirty-seven months (as described
in the NIH
Grants Policy Statement), except for submission:

To an RFA of an application that was submitted previously as an
investigator-initiated application but not paid;

Of an investigator-initiated application that was originally
submitted to an RFA but not paid; or

Of an application with a changed grant activity code.

Section IV. Application
and Submission Information

1. Requesting an
Application Package

Applicants must download the SF424 (R&R) application
package associated with this funding opportunity using the “Apply for Grant
Electronically” button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in
the SF424
(R&R) Application Guide, except where instructed in this funding
opportunity announcement to do otherwise. Conformance to the requirements in
the Application Guide is required and strictly enforced. Applications that are
out of compliance with these instructions may be delayed or not accepted for
review.

Although a letter of intent is not required, is not binding,
and does not enter into the review of a subsequent application, the information
that it contains allows IC staff to estimate the potential review workload and
plan the review.

By the date listed in Part 1. Overview
Information, prospective applicants are asked to submit a letter of intent
that includes the following information:

All page limitations described in the SF424 Application
Guide and the Table of
Page Limits must be followed.

Required and Optional Components

The forms package associated with this FOA includes all
applicable components, required and optional. Please note that some
components marked optional in the application package are required for
submission of applications for this FOA. Follow all instructions in the SF424
(R&R) Application Guide to ensure you complete all appropriate “optional”
components.

SF424(R&R) Cover

All instructions in the SF424 (R&R) Application Guide
must be followed.

SF424(R&R) Project/Performance Site Locations

All instructions in the SF424 (R&R) Application Guide
must be followed.

SF424(R&R) Other Project Information

All instructions in the SF424 (R&R) Application Guide
must be followed.

SF424(R&R) Senior/Key Person Profile

All instructions in the SF424 (R&R) Application Guide
must be followed.

R&R or Modular Budget

All instructions in the SF424 (R&R) Application Guide
must be followed.

PHS 398 Cover Letter

All instructions in the SF424 (R&R) Application Guide
must be followed.

PHS 398 Cover Page Supplement

All instructions in the SF424 (R&R) Application Guide
must be followed.

PHS 398 Research Plan

All instructions in the SF424 (R&R) Application Guide
must be followed, with the following additional instructions:

Appendix: Do not use the Appendix to circumvent page limits. Follow all
instructions for the Appendix as described in the SF424 (R&R) Application
Guide.

Foreign Institutions

Foreign (non-U.S.) institutions must follow policies
described in the NIH
Grants Policy Statement, and procedures for foreign institutions described
throughout the SF424 (R&R) Application Guide.

3. Submission Dates and
Times

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit applications
before the due date to ensure they have time to make any application
corrections that might be necessary for successful submission.

Organizations must submit applications to Grants.gov, the online portal to find and apply for grants across all Federal agencies. Applicants must then complete the submission process by tracking the
status of the application in the eRA Commons, NIH’s electronic system for grants
administration. NIH and Grants.gov systems check the application against many
of the application instructions upon submission. Errors must be corrected and a
changed/corrected application must be submitted to Grants.gov on or before the application
due date. If a Changed/Corrected application is submitted after the deadline,
the application will be considered late.

Applicants
are responsible for viewing their application before the due date in the eRA
Commons to ensure accurate and successful submission.

Information on the submission process and a definition of
on-time submission are provided in the SF424 (R&R) Application Guide.

For assistance with your electronic application or for more information on the electronic submission
process, visit Applying
Electronically.

Important
reminders:All PD(s)/PI(s) must include their eRA Commons ID in the
Credential fieldof the Senior/Key Person Profile Component of the
SF424(R&R) Application Package. Failure to register in the Commons
and to include a valid PD/PI Commons ID in the credential field will prevent
the successful submission of an electronic application to NIH. See Section III of this FOA for information on
registration requirements.

The applicant organization must ensure that the DUNS number it provides on the
application is the same number used in the organization’s profile in the eRA
Commons and for the System for Award Management. Additional information may be
found in the SF424 (R&R) Application Guide.

Upon receipt, applications will be evaluated for completeness
by the Center for Scientific Review, NIH. Applications that are incomplete will
not be reviewed.

Post Submission Materials

Applicants are required to follow the instructions for
post-submission materials, as described in NOT-OD-10-115.

Section V. Application Review Information

1.
Criteria

Only the review criteria described below will be considered
in the review process. As part of the NIH mission,
all applications submitted to the NIH in support of biomedical and behavioral
research are evaluated for scientific and technical merit through the NIH peer
review system.

Overall Impact

Reviewers will provide an overall impact score to reflect
their assessment of the likelihood for the project to exert a sustained,
powerful influence on the research field(s) involved, in consideration of the
following review criteria and additional review criteria (as applicable for the
project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in
the determination of scientific merit, and give a separate score for each. An
application does not need to be strong in all categories to be judged likely to
have major scientific impact. For example, a project that by its nature is not
innovative may be essential to advance a field.

Significance

Does the project address an important problem or a
critical barrier to progress in the field? If the aims of the project are
achieved, how will scientific knowledge, technical capability, and/or clinical
practice be improved? How will successful completion of the aims change the
concepts, methods, technologies, treatments, services, or preventative
interventions that drive this field?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other
researchers well suited to the project? If Early Stage Investigators or New
Investigators, or in the early stages of independent careers, do they have
appropriate experience and training? If established, have they demonstrated an
ongoing record of accomplishments that have advanced their field(s)? If the
project is collaborative or multi-PD/PI, do the investigators have
complementary and integrated expertise; are their leadership approach,
governance and organizational structure appropriate for the project?

Innovation

Does the application challenge and seek to shift
current research or clinical practice paradigms by utilizing novel theoretical
concepts, approaches or methodologies, instrumentation, or interventions? Are
the concepts, approaches or methodologies, instrumentation, or interventions
novel to one field of research or novel in a broad sense? Is a refinement,
improvement, or new application of theoretical concepts, approaches or
methodologies, instrumentation, or interventions proposed?

Approach

Are the overall strategy, methodology, and analyses
well-reasoned and appropriate to accomplish the specific aims of the project?
Are potential problems, alternative strategies, and benchmarks for success
presented? If the project is in the early stages of development, will the
strategy establish feasibility and will particularly risky aspects be managed?

If the project involves clinical research, are the plans for 1) protection of
human subjects from research risks, and 2) inclusion of minorities and members
of both sexes/genders, as well as the inclusion of children, justified in terms
of the scientific goals and research strategy proposed?

Environment

Will the scientific environment in which the work
will be done contribute to the probability of success? Are the institutional
support, equipment and other physical resources available to the investigators
adequate for the project proposed? Will the project benefit from unique
features of the scientific environment, subject populations, or collaborative
arrangements?

Additional Review Criteria

As applicable for the project proposed, reviewers will
evaluate the following additional items while determining scientific and
technical merit, and in providing an overall impact score, but will not give
separate scores for these items.

Core set of reporting standards

Randomization

Are the animals
assigned randomly to the various experimental groups, and are the methods of
randomization reported?

Is the
data collected and processed randomly or is it appropriately blocked?

Blinding

Is there
allocation concealment? The investigator should be unaware of the group to
which the next animal taken from a cage will be allocated.

Is there
blinded conduct of the experiment? Animal caretakers and investigators
conducting the experiments should be blinded to the allocation sequence.

Is there
blinded assessment of outcome? Investigators assessing, measuring or
quantifying experimental outcomes should be blinded to the intervention.

Sample-size
estimation

Has an
appropriate sample size been computed when the study was designed and are the
statistical methods of computation reported?

Do statistical
methods take into account multiple evaluations of the data when an interim evaluation
is carried out?

Data
handling

Have rules
for stopping data collection been defined in advance?

Have criteria
for inclusion and exclusion of data been established prospectively?

Are
methods described for how outliers will be defined and handled? Will any data be
removed before the analysis is reported?

Have the
primary end points been prospectively selected? If multiple end points are to
be assessed, have appropriate statistical corrections been applied?

Do investigators
have a plan to report on data missing because of attrition or exclusion?

Have pseudo
replicate issues been considered during study design and analysis?

Have investigators
described how they will report how often a particular experiment was performed
and whether results were substantiated by repetition under a range of
conditions?

Protections for Human Subjects

For research that involves human subjects but does
not involve one of the six categories of research that are exempt under 45 CFR
Part 46, the committee will evaluate the justification for involvement of human
subjects and the proposed protections from research risk relating to their
participation according to the following five review criteria: 1) risk to
subjects, 2) adequacy of protection against risks, 3) potential benefits to the
subjects and others, 4) importance of the knowledge to be gained, and 5) data
and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or
more of the six categories of research that are exempt under 45 CFR Part 46,
the committee will evaluate: 1) the justification for the exemption, 2) human
subjects involvement and characteristics, and 3) sources of materials. For additional
information on review of the Human Subjects section, please refer to the Human
Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and
Children

When the proposed project involves clinical research,
the committee will evaluate the proposed plans for inclusion of minorities and
members of both genders, as well as the inclusion of children. For additional
information on review of the Inclusion section, please refer to the Human
Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live
vertebrate animals as part of the scientific assessment according to the
following five points: 1) proposed use of the animals, and species, strains,
ages, sex, and numbers to be used; 2) justifications for the use of animals and
for the appropriateness of the species and numbers proposed; 3) adequacy of
veterinary care; 4) procedures for limiting discomfort, distress, pain and
injury to that which is unavoidable in the conduct of scientifically sound
research including the use of analgesic, anesthetic, and tranquilizing drugs
and/or comfortable restraining devices; and 5) methods of euthanasia and reason
for selection if not consistent with the AVMA Guidelines on Euthanasia. For
additional information on review of the Vertebrate Animals section, please
refer to the Worksheet
for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures
proposed are potentially hazardous to research personnel and/or the
environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

For Resubmissions, the committee will evaluate the
application as now presented, taking into consideration the responses to
comments from the previous scientific review group and changes made to the
project.

Renewals

For Renewals, the committee will consider the
progress made in the last funding period.

Revisions

For Revisions, the committee will consider the
appropriateness of the proposed expansion of the scope of the project. If the
Revision application relates to a specific line of investigation presented in
the original application that was not recommended for approval by the committee,
then the committee will consider whether the responses to comments from the
previous scientific review group are adequate and whether substantial changes
are clearly evident.

Additional Review Considerations

As applicable for the project proposed, reviewers will
consider each of the following items, but will not give scores for these items,
and should not consider them in providing an overall impact score.

Applications from Foreign
Organizations

Reviewers will assess whether the project presents
special opportunities for furthering research programs through the use of
unusual talent, resources, populations, or environmental conditions that exist
in other countries and either are not readily available in the United States or
augment existing U.S. resources.

Select Agent Research

Reviewers will assess the information provided in
this section of the application, including 1) the Select Agent(s) to be used in
the proposed research, 2) the registration status of all entities where Select
Agent(s) will be used, 3) the procedures that will be used to monitor
possession use and transfer of Select Agent(s), and 4) plans for appropriate
biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will consider whether the budget and the
requested period of support are fully justified and reasonable in relation to
the proposed research.

2. Review and Selection
Process

Applications will be evaluated for scientific and technical
merit by (an) appropriate Scientific Review Group(s), convened by the Center for Scientific Review (CSR), in accordance with NIH peer
review policy and procedures, using the stated review
criteria. Assignment to a Scientific Review Group will be shown in the eRA
Commons.

As part of the scientific peer review, all applications:

May undergo a selection process in which only those applications
deemed to have the highest scientific and technical merit (generally the top
half of applications under review) will be discussed and assigned an overall impact
score.

Will receive a written critique.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications
will compete for available funds with all other recommended applications. Following initial peer review, recommended applications will receive a second level of
review by the National Advisory Child Health and Human Development (NACHHD)
Council. The following will be considered in making funding decisions:

Scientific and technical merit of the proposed project as
determined by scientific peer review.

Availability of funds.

Relevance of the proposed project to program priorities.

3. Anticipated Announcement
and Award Dates

After the peer review of the application is completed, the
PD/PI will be able to access his or her Summary Statement (written critique)
via the eRA
Commons.

If the application is under consideration for funding, NIH
will request "just-in-time" information from the applicant as
described in the NIH
Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided
to the applicant organization for successful applications. The NoA signed by
the grants management officer is the authorizing document and will be sent via
email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection
of an application for award is not an authorization to begin performance. Any
costs incurred before receipt of the NoA are at the recipient's risk. These
costs may be reimbursed only to the extent considered allowable pre-award costs.

When multiple years are involved, awardees will be required
to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR)
and financial statements as required in the NIH
Grants Policy Statement.

A final progress report, invention
statement, and the expenditure data portion of the Federal Financial Report are
required for closeout of an award, as described in the NIH
Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of
2006 (Transparency Act), includes a requirement for awardees of Federal grants
to report information about first-tier subawards and executive compensation
under Federal assistance awards issued in FY2011 or later. All awardees of
applicable NIH grants and cooperative agreements are required to report to
the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH
Grants Policy Statement for additional information on this reporting
requirement.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity
and welcome the opportunity to answer questions from potential applicants.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and
under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.